DESCRIPTION: The long term objective of these studies is to determine the forces that cause sex differences in brain and behavior. For more than 40 years, the central concept of sexual differentiation has held that all sex differences in brain and behavior result from the peripheral actions of gonadal steroid hormones. Recent research on the neural circuit for song in the zebra finch conflicts with this classic dogma, and suggests the alternative hypothesis that some sex-specific gene products may act directly on brain to induce sex-specific neural development, independent of the action of gonadal hormones. The proposed experiments will begin to test this novel concept. (1) Two sex chromosome-linked genes, which are expressed in female but not male brain have been identified. The genes are candidates for genetic signals that induce sexual differentiation. These genes and their relatives will be cloned and characterized to determine how their expression is regulated according to sex, tissue, developmental age, and by steroid hormones. (2) Other genes, thought to be involved in sexual differentiation downstream of the initiating event, will be studied to determine when and where their mRNAs are expressed in the brain. (3) SOX genes known in other species to be involved in sexual differentiation of non-neural tissues, will be studied to determine if they are expressed in a sexually dimorphic manner. (4) Sex-specific dissociated neural cell cultures will be prepared from the brains of neonatal animals to determine if they exhibit sex differences in the expression of specific antigens and mRNAs, in order to develop in vitro model systems amenable for the study of factors influencing sexual differentiation. The proposed research will contribute significantly to an understanding of the principles of sexual differentiation of the brain and mechanisms of steroid hormone action on the brain. At issue are the molecular mechanisms by which male and female brains differ, which is highly relevant to biological basis of abnormalities of sexual differentiation, and to the explanation of sex differences in neural and psychiatric disease (e.g., Alzheimer's and Multiple Sclerosis). Moreover, the proposed studies bear strongly on the regulation of steroid hormone action on the nervous system, during reproduction and stress.